Therapeutics

KP405

Tools

Back to the Top

Overview

Name: KP405
Synonyms: DA5-CH
Chemical Name: YXEGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSKRRQRRKKRGY-NH2; X is aminoisobutyric acid
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Kariya Pharmaceuticals ApS

Background

KP405 is a dual incretin receptor agonist that is being developed to treat Parkinson’s disease. It acts on the glucagon-like peptide 1 (GLP-1) receptor and the gastric inhibitory peptide (GIP) receptor. Both GLP-1 and GIP receptors regulate blood sugar and appetite. GLP-1 agonists are widely used to treat diabetes and obesity, and show some beneficial effects in animal models of Alzheimer's and Parkinson’s diseases. They have been reported to resensitize insulin signaling, normalize energy utilization, improve mitochondrial function, reduce chronic inflammation, and lengthen neuron survival. The dual GLP-1/GIP agonist tirzepatide is approved to treat diabetes, obesity, and sleep apnea.

Several GLP1 agonists are in trials for PD or AD , but the ability of these large-peptide-derived drugs to enter the brain varies (e.g., exenatide, semaglutide, liraglutide, lixisenatide).  KP405 is a smaller, 50-amino-acid peptide that was modified to improve brain penetration (Hölscher, 2018). It crosses the blood-brain barrier better than semaglutide or tirzepatide after intravenous injection in male mice (Rhea et al., 2023; Salameh et al., 2020).

KP405 reportedly improved memory, amyloid and tau pathology, synaptic and mitochondrial function, and was neuroprotective in APP/PS1 and streptozotocin models (Cao et al., 2018; Li et al., 2020). In animal models of PD, it is claimed to be more efficacious than semaglutide, liraglutide, or the exendin-4 analog NLY01 at improving motor impairment, α-synuclein pathology, dopamine neuron loss, inflammation, autophagy, and mitochondrial activity (Zhang et al., 2022; Zhang et al., 2023; Lv et al., 2021). Preclinical data presented at the April 2025 AD/PD conference claimed superiority to tirzepatide for dopamine neuron protection and inflammation. When given intranasally to APP/PS1 mice, KP405 did not distribute through the brain (Abdulhameed et al., 2024).

Findings

In August 2024, Phase1 began with a single- and multiple-ascending-dose study in healthy adults and people with Parkinson’s disease. Participants receive the drug by injection. Primary outcomes are adverse events, safety measures, pharmacokinetics and pharmacodynamic measure including pupillometry, EEG, food intake, and appetite. The trial plans to enroll 88 people at one site in England, and finish in December 2025.

For details on KP405 trials, see clinicaltrials.gov.

Last Updated: 20 Jun 2025

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Therapeutics Citations

  1. Exenatide
  2. Semaglutide
  3. Liraglutide
  4. Lixisenatide

Paper Citations

  1. Hölscher C. Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models. Neuropharmacology. 2018 Jul 1;136(Pt B):251-259. Epub 2018 Jan 31 PubMed.
  2. Rhea EM, Babin A, Thomas P, Omer M, Weaver R, Hansen K, Banks WA, Talbot K. Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer's and Parkinson's diseases. Tissue Barriers. 2023 Dec 14;:2292461. PubMed.
  3. Salameh TS, Rhea EM, Talbot K, Banks WA. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics. Biochem Pharmacol. 2020 Oct;180:114187. Epub 2020 Aug 2 PubMed. Correction.
  4. Cao Y, Hölscher C, Hu MM, Wang T, Zhao F, Bai Y, Zhang J, Wu MN, Qi JS. DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease. Eur J Pharmacol. 2018 May 15;827:215-226. Epub 2018 Mar 15 PubMed.
  5. Li C, Liu W, Li X, Zhang Z, Qi H, Liu S, Yan N, Xing Y, Hölscher C, Wang Z. The novel GLP-1/GIP analogue DA5-CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD. Brain Behav. 2020 Mar;10(3):e01505. Epub 2020 Jan 20 PubMed.
  6. Zhang L, Li C, Zhang Z, Zhang Z, Jin QQ, Li L, Hölscher C. DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson's Disease Rat Model. Parkinsons Dis. 2022;2022:1428817. Epub 2022 Nov 14 PubMed.
  7. Zhang Z, Shi M, Li Z, Ling Y, Zhai L, Yuan Y, Ma H, Hao L, Li Z, Zhang Z, Hölscher C. A Dual GLP-1/GIP Receptor Agonist Is More Effective than Liraglutide in the A53T Mouse Model of Parkinson's Disease. Parkinsons Dis. 2023;2023:7427136. Epub 2023 Sep 25 PubMed.
  8. Lv M, Xue G, Cheng H, Meng P, Lian X, Hölscher C, Li D. The GLP-1/GIP dual-receptor agonist DA5-CH inhibits the NF-κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP-1 single-receptor agonist NLY01. Brain Behav. 2021 Aug;11(8):e2231. Epub 2021 Jun 14 PubMed.
  9. Abdulhameed N, Babin A, Hansen K, Weaver R, Banks WA, Talbot K, Rhea EM. Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease. Alzheimers Res Ther. 2024 Aug 1;16(1):173. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

No Available Further Reading